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Whether the intrinsic epileptogenicity of hypothalamic hamartomas (HH) is responsible for the entire clinical spectrum of epileptic, neuropsychological and behavioural disorders associated with HH, remains an open issue, in as much as morphologically similar HH can be associated with dramatically different seizure types and cognitive outcomes. The aim of this study was to investigate brain glucose metabolism in patients with epileptogenic HH, in an attempt to identify signs of focal cortical and subcortical dysfunction which might correlate with other clinical data. We have studied five patients with epileptogenic HH using [18F]‐fluorodesoxyglucose and positron emission tomography (FDG‐PET). All our patients also underwent an optimal MRI and a video‐EEG monitoring, as well as an intra‐cranial EEG recording in one of them. The anatomical distribution of FDG‐PET abnormalities was compared to that of interictal and ictal electroclinical findings. All five patients demonstrated focal hypometabolism, ipsilateral to the predominant EEG abnormalities and side of HH. Hypometabolic areas greatly varied between patients, but were grossly concordant with the cortical regions suspected to participate in the ictal discharges in each individual. Epileptogenic hypothalamic hamartomas are usually associated with focal cortical hypometabolism in regions which might participate in the overall HH‐driven epileptic network. Whether these cortical abnormalities only reflect the propagation of ictal discharges, or a potentially independent seizure onset zone remains unknown.

The roles of mu, delta and kappa opioid receptor subtypes in spinal morphine-induced antinociception were investigated. A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. Recruitment curves were built by varying the stimulus intensity from 0 to 7x threshold and temporal evolutions were studied by using a constant level of stimulus intensity (3x threshold). Intrathecal administration of naloxone, Cys2-Tyr3-Orn5-Pen7 amide (mu opioid receptor antagonist) and nor-binaltorphimine (nor-BNI, a kappa opioid receptor antagonist) completely antagonized the depression of the C-fiber reflex induced by 4 nmol of intrathecal morphine, whereas the antagonistic effect of naltrindole (a delta receptor antagonist) was limited, with a ceiling effect of 56%. The AD50 were 12 pmol and 1, 4.3 and 39 nmol for Cys2-Tyr3-Orn5-Pen7 amide, naloxone, nor-BNI and naltrindole, respectively. When injected alone, only naltrindole induced a short-duration depressive effect. Intrathecal administration of DAGO resulted in a depressive effect on the C-fiber reflex in a dose-dependent manner; for a stimulus intensity of 3x threshold, the ED50 was 9 pmol. DAGO was found to be 60 times more potent than morphine. Interestingly, nor-BNI, at doses which reversed the blockade of the C-fiber reflex by morphine, also reversed the effects of an equipotent dose of DAGO, which suggested an action on a mu receptor subtype.

A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. The temporal evolution of the response was studied using a constant stimulus intensity (3 x threshold) and recruitment curves were built by varying stimulus intensity from 0 to 7 x threshold. The i.v. administration of aspirin, indomethacin, ketoprofen, paracetamol (= acetaminophen) and lysine clonixinate resulted in dose-dependent depressions of the C-fiber reflex by up to 30 to 40%. By contrast, saline was ineffective. High doses of the effective drugs that produced large disturbances in heart rate and/or acid-base equilibrium were not considered in the pharmacological analysis. When a constant level of stimulation was used, different dose-dependent profiles of drug action were observed. Aspirin induced a slow and gradual depression, although indomethacin, ketoprofen and paracetamol produced a peak effect within the first 10-min period and then reached a steady state phase for up to 30 min. The depressive effects of lysine clonixinate appeared more stable. When recruitment curves were built with a range of nociceptive stimulus intensities, all the drugs produced a dose-dependent decrease in the slopes and the areas under the recruitment curves without any major modification in the thresholds. The order of potency was the same for both stimulation paradigms, e.g., aspirin < paracetamol < lysine clonixinate = ketoprofen < indomethacin. It is concluded that NSAID elicit significant antinociceptive effects at a central level, which do not depend on the existence of a hyperalgesic or inflammatory state.

1. Extracellular recordings were made from fourteen non‐noxious only and nineteen convergent neurones in trigeminal nucleus caudalis of halothane‐anaesthetized rats. All the neurones studied were excited by the continuous micro‐electrophoretic ejection of an excitatory amino acid, DL‐homocysteic acid (DLH), with mean currents of 38.0 +/‐ 7.2 and 39.8 + 6.5 nA producing steady discharges of 35.0 +/‐ 3.3 and 31.8 +/‐ 1.3 spikes/s from the non‐noxious only and convergent neurones respectively. 2. The repeated percutaneous application (100 trials; 0.66 Hz) of single square‐wave stimuli (10 mA; 2 ms) to the tail always induced a biphasic depression of the activity of the convergent, but never of the non‐noxious only, neurones. Both the early and late components of this inhibition occurred at shorter latencies when the base rather than the tip of the tail was stimulated. Differences in latencies from the two sites of stimulation (100 mm apart) were used to estimate the conduction velocities of the peripheral fibres which were triggering the inhibitions. 3. The cumulated results showed that, for the onset of the earlier component of the inhibition, the mean difference between the latencies from the two sites of stimulation was 13.6 +/‐ 1.9 ms, corresponding to a peripheral conduction velocity of 7.3 +/‐ 0.3 m/s, which is in the A delta‐fibre range. For the onset of the late component of inhibition, the mean difference was 147.7 +/‐ 14.9 ms, corresponding to a peripheral conduction velocity of 0.68 +/‐ 0.07 m/s, which is in the C‐fibre range. 4. When currents of different intensities were applied percutaneously to the two stimulation sites, the thresholds for obtaining the A delta component were in the range 0.25‐0.5 mA whereas the C component appeared with currents 1‐2 mA. A clear relationship between current intensity and magnitude of inhibition was observed in the 0.25‐2 mA range for the A delta component and in the 1‐5 mA range for the C component. 5. In an additional series of experiments recordings were made from eleven convergent neurones in the dorsal horn of the lumbar spinal cord. By using essentially the same experimental procedure the effects of repetitive application (100 trials, 0.66 Hz) of percutaneous electrical stimuli (1 or 10 mA, 2 ms) applied to the muzzle, were studied on the steady discharges (42.3 +/‐ 5.4 spikes/s) induced by DLH. The application of the 10 mA stimuli induced a biphasic depression of activity, whereas only an early component was observed following 1 mA stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

1. In order to study descending influences of the brain stem upon the transmission of nociceptive messages at the spinal level, the activities of lumbar lamina V dorsal horn cells, induced by intra‐arterial injection of brandykinin into the limbs, were recorded in unanaesthetized cats in both decerebrate and temporary spinal states (reversible cold block applied at the thoracic level). 2. In the decerebrate state, the intra‐arterial injection of bradykinin had little or no effect. 3. During the reversible spinalization, the effects of bradykinin were revealed or considerably enhanced. As described in a previous study, in the C1‐transected cat, three types of effects were encountered: excitatory, inhibiitory and mixed (inhibitory‐excitatory). 4. These modifications observed after spinalization were generally associated with a large increase of the spontaneous firing rate. 5. These results emphasize, in the decerebrate cat, the importance of descending inhibitory controls exerted by the brain stem upon the transmission of nonciceptive messages at the spinal cord level.

1. Recordings were made from thirty‐nine convergent neurones in the lumbar enlargement of the rat spinal cord. These neurones were activated by both innocuous and noxious stimuli applied to their excitatory receptive fields located on the extremity of the ipsilateral hind paw. Transcutaneous application of suprathreshold 2 ms square‐wave pulses to the centre of the receptive field resulted in responses to A‐ and C‐fibre activation being observed; a mean of 18.8 +/‐ 1.8 C‐fibre latency spikes was evoked per stimulus. This type of response was inhibited by applying noxious conditioning stimuli to heterotopic body areas; immersing the tail in a 52 degrees C water‐bath caused a mean 54.5 +/‐ 2.3% inhibition of the C‐fibre‐evoked response; such inhibitory processes have been termed diffuse noxious inhibitory controls (d.n.i.c.). 2. The effects of microinjections of morphine (5 micrograms; 0.2 microliter) on both the unconditioned C‐fibre‐evoked response and inhibitory processes triggered from the tail were investigated in an attempt to answer two questions: (a) does morphine increase tonic descending inhibitory processes and (b) what are the effects of morphine on descending inhibitory processes triggered by noxious stimuli? 3. The predominant effect of periaqueductal grey matter (p.a.g.) morphine on the C‐fibre‐evoked responses was a facilitation: 51% of cells had their C‐fibre‐evoked responses increased by morphine (by roughly 50%); 31% of cells were not influenced while the remaining 18% of units were depressed; however the cells classified as depressed were only marginally so. No clear relationships were found either between the microinjection sites in the p.a.g. and their corresponding effects or between the number of C‐fibre‐spikes evoked in the control sequences and the subsequent effect of morphine. 4. While d.n.i.c. was not altered by morphine in 56% of cases, it was clearly reduced in the remaining cells. The effects were immediate but peaked at 40 min following the microinjection (a mean 77% reduction) and then returned towards control values. All but three of the corresponding microinjection sites were such as to include the medio‐ventral p.a.g. including the nucleus raphé dorsalis. In contrast none of the cases where d.n.i.c. was unaltered included microinjection sites in this region. 5. No relationship was found between the changes in d.n.i.c. and the number of spikes evoked in the control sequences, or the changes in the C‐fibre responses. 6. Autoradiographic controls using [3H]morphine showed a large diffusion of the drug within an area of about 0.75 mm around the tip of the cannula.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects on C fiber evoked activity in lumbar dorsal horn convergent neurones of i.v. morphine alone, of Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET) alone or of either of these drugs in association with 5-deoxyadenosylcobalamine (dibencozide) were investigated in anesthetized rats. Both morphine and DTLET depressed the neuronal responses in a dose-related fashion, with the former requiring lower doses. Although dibencozide alone was devoid of any effect, it significantly enhanced the depressive effects of all doses of morphine tested and of the lower two doses of DTLET. It is concluded that dibencozide enhances the spinal depression of nociceptive information elicited by mu and delta opioid agonists. This drug could provide a useful tool for the study of interactions between opioids and opioids receptors. It is also suggested that dibencozide could be useful in clinical practice for reducing the dosage of opioids.

1. In anesthetized rats, recordings were made within the medullary subnucleus reticularis dorsalis (SRD) from neurons that exhibited convergence of nociceptive inputs from the entire body. Neurons with total nociceptive convergence (TNC) responded to suprathreshold percutaneous electrical stimuli (2-ms duration) with an early and a late peak due to activation of A delta- and C-fibers, respectively, no matter which part of the body was stimulated. Neurons with partial nociceptive convergence (PNC) responded to the same stimuli with an A delta-peak regardless of which part of the body was stimulated and with a C-peak of activation from some, mainly contralateral, parts of the body. The characteristics of the responses of these neurons to the application of graded intensities of electrical, thermal, and mechanical stimuli were analyzed. 2. All TNC neurons and 85% of PNC neurons responded to A delta- and C-fiber activation following percutaneous electrical stimulation of the contralateral hindpaw. With regard to A delta-fiber-evoked responses, a linear relationship between the logarithm of the applied current and the magnitude of the responses was found within the 0.25- to 6.0-mA and 0.5- to 24-mA ranges for TNC and PNC neurons, respectively; however, these curves were essentially similar. With regard to C-fiber-evoked responses, such a linear relationship was found within the 1.5- to 6.0-mA range for both types of SRD neurons, although the TNC neurons presented larger C-fiber-evoked responses than did the PNC neurons. 3. TNC and PNC neurons linearly increased their discharges during the application of noxious thermal stimuli to the contralateral hindpaw within the range 44-52 degrees C; the mean responses evoked by noxious heat from TNC neurons were of higher magnitude than those from PNC neurons. The majority of SRD neurons presented long-lasting afterdischarges, especially with the highest temperature employed (52 degrees C). 4. TNC neurons monotonically increased their discharges during graded mechanical or thermal stimulation of the tail. When mechanical stimuli were applied, a linear relationship was found between the logarithm of the strength of the mechanical stimulus and the neuronal discharges, in the 5.3- to 7.4-N/cm2 range. With thermal stimulation, TNC neurons linearly increased their discharges in the 44-52 degrees C range. When increasing amounts of the tail were immersed in a 50 degrees C waterbath, TNC neurons increased their discharges within a restricted range of tail surface areas (0.9-5.7 cm2); further increases in the stimulated surface size were not followed by increases in firing rate.(ABSTRACT TRUNCATED AT 400 WORDS)

1. It has previously been shown that, in normal humans, heterotopic painful thermal conditioning stimuli induce parallel increase in the thresholds of a spinal nociceptive flexion reflex (RIII reflex) and the concurrent sensation of pain elicited by electrical stimulation of the sural nerve. On the basis of analogous animal studies, we proposed that such phenomena could be related to diffuse noxious inhibitory controls (DNIC), which have been described in the rat. The present study, which was carried out on normal volunteer subjects, was particularly concerned with the extent and temporal characteristics of the depressive effects of DNIC triggered by painful thermal stimuli on RIII reflex activity. In addition, because it was possible that these depressive effects could have resulted from a direct postsynaptic inhibition of motoneurons, a second part of the study was aimed at determining whether or not the heterotopic noxious thermal stimuli also affected the excitability of alpha-motoneurons, as monitored by the monosynaptic Hoffmann reflex (H reflex) technique. 2. In the 11 subjects under study, application of moderate, nonnoxious temperatures (40-44 degree C) to the contralateral hand (via a thermoregulated and agitated waterbath) did not modify the RIII reflex nor the associated sensation of pain. By contrast noxious temperatures clearly depressed the RIII reflex and the concurrent sensation of pain, both during and after the conditioning procedure (CP), in a direct linear relationship to the temperature of the waterbath in the 45-47 degree C range; the maximal depressive effect was observed with the highest conditioning temperature. A significant relationship was also found between the extent of the RIII depression during the CP and that during a 10-min period of post-CP observation. 3. The depressive effects observed on both the RIII reflex and pain were not associated with clear change in autonomic functions. Respiration remained stable during the sessions, with no significant relationship between the temperatures of the waterbath and respiratory rate. Heart rate was slightly but significantly increased during the immersion of the hand in the 46 or 47 degree C waterbaths; this increase, however, ceased with the end of CP. 4. Application of thermal conditioning stimuli produced a slight but nonsignificant increase of the monosynaptic H reflex during the first minute of CP, no matter what was the temperature of the waterbath. However, there were no subsequent variations during the 6-min period of post-CP observation.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of the novel mixed peptidase inhibitor, kelatorphan [N-(R)-3-(N-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl)-L-alanine], were compared to those of a combination of the potent "enkephalinase" inhibitor thiorphan and the nonselective aminopeptidase inhibitor bestatin, on the catabolism of [3H]Met-enkephalin and on the release of endogenous Met-enkephalin by the rat spinal cord in vitro and in vivo. At 20 microM, kelatorphan almost prevented completely the degradation of exogenous [3H] Met-enkephalin by slices of the dorsal zone of the lumbar enlargement. Similarly, the addition of 20 microM kelatorphan to a [3H] Met-enkephalin-containing artificial cerebrospinal fluid superfusing the whole spinal cord of halothane-anesthetized rats efficiently protected the exogenous peptide from enzymatic degradation. In contrast, in the same in vitro and in vivo models, thiorphan (1 microM) or bestatin (20 microM) alone was inactive, and only their combination induced a significant protection of the exogenous peptide. In vitro and in vivo, kelatorphan (20 microM) increased markedly the spontaneous outflow of endogenous Met-enkephalin-like material as well as the peptide overflow due to K+-induced depolarization (in vitro and in vivo) or noxious stimulation (in vivo). Under similar conditions, thiorphan (1 microM) plus bestatin (20 microM) also enhanced the efflux of Met-enkephalin-like material, but generally to a lower extent than kelatorphan. Compared to thiorphan plus bestatin, kelatorphan exerts additional inhibitory effects on dipeptidylaminopeptidase activity and the present results could indicate that this enzyme also may be involved in the inactivation of extracellular Met-enkephalin at the spinal level in rats.

A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. The temporal evolution of the response was studied by using a constant stimulus intensity (3 x threshold) and recruitment curves were built by varying the stimulus intensity from 0 to 7 x threshold. Low (0.5-1 mg/kg) and high doses (4-10 mg/kg) of i.v. morphine induced a facilitation and a depression of the C-fiber reflex, respectively, in a dose-dependent manner. The ED50 (95% confidence limit) for the depressive effect with a stimulus intensity of 3 x control threshold was 3.8 (3.1-4.8) mg/kg. Increasing the stimulus intensity was associated with a shift of the dose-response curve to the right, without a change of slope. In the 1.5 to 7 x threshold range, ED50 were linearly related to the stimulus intensity. Intravenous naloxone (0.4 mg/kg) completely antagonized the facilitation or depression induced by morphine. Low doses (1-10 micrograms/kg; i.v.) of buprenorphine facilitated the reflex in a fashion similar to morphine. Higher doses (30-1000 micrograms/kg; i.v.) elicited a biphasic effect on the C-fiber reflex: depressive and facilitatory with weak and strong stimulus intensities, respectively. These results are discussed in terms of there being an intrinsic efficacy for the depressive effects of morphine and buprenorphine and of their clinical potencies. Various hypotheses are suggested regarding the facilitations of the C-fiber reflex.

A C-fiber reflex elicited by electrical stimulation within the territory of the ipsilateral sural nerve, was recorded from the biceps femoris muscle in anesthetized rats. The temporal evolution of the reflex was studied using a constant level of stimulus intensity (3 x threshold) and recruitment curves were built by varying stimulus intensity from 0 to 7 x threshold. Intrathecal doses of buprenorphine in the 0.2 to 10 micrograms range, elicited a facilitation of the C-fiber reflex in a dose-dependent manner. A large dose (100 micrograms) depressed but did not block the reflex. Intracerebroventricular doses of buprenorphine in the 0.1 to 10 micrograms range, facilitated the C-fiber reflex. A higher dose (100 micrograms) elicited a biphasic effect: depressive when the stimulus intensity was weak and facilitatory when the stimulus intensity was strong. It is concluded that the antinociceptive properties of buprenorphine cannot be related to a direct or indirect depressive spinal effect. In terms of spinal and supraspinal effects of buprenorphine, it is likely that buprenorphine facilitates the C-fiber reflex via a supraspinal mechanism that acts on sensory and/or motor components of the reflex arc although the depression of the reflex involves a spinal mechanism. The lipophilic properties of buprenorphine could explain a substantial diffusion from its spinal injection site to the brain. From a clinical standpoint, this study confirms that intrathecal administration of buprenorphine is an inadequate way of accessing spinal opioid receptors.

Recordings were made from convergent neurons in the lumbar dorsal horn of the rat. These neurons were activated by both innocuous and noxious stimuli applied to their excitatory receptive fields located on the extremity of the ipsilateral hindpaw. Transcutaneous application of suprathreshold 2-msec square-wave pulses to the center of the receptive field resulted in responses to A- and C-fiber activation being observed: 27.2 +/- 2.2 (mean +/- S.E.M.) C-fiber latency spikes were evoked per stimulus. This type of response was inhibited by applying noxious conditioning stimuli to heterotopic areas of the body; in particular, immersing the tail in a 52 degrees C waterbath caused a 74.2 +/- 2.0% inhibition of the C-fiber evoked responses; such inhibitory processes have been termed diffuse noxious inhibitory controls (DNIC). The effects of microinjections of morphine (0.6-40 micrograms; 2 microliter) within the 3rd ventricle on both the unconditioned C-fiber-evoked responses and the inhibitory processes triggered from the tail were investigated in an attempt to answer two questions: 1) does i.c.v. morphine increase tonic descending inhibitory processes? and 2) what are the effects of i.c.v. morphine on descending inhibitory processes triggered phasically by noxious stimuli? The predominant effect of i.c.v. morphine on the C-fiber-evoked responses was a facilitation (17 of 26 cases). Such a facilitation was dose-related in the 0.6 to 40 microgram range and naloxone reversible; it plateaued from 20 min after the microinjection. No clear relationship was found between the number of C-fiber evoked responses in the control sequences and the subsequent effect of i.c.v. morphine. Intracerebroventricular morphine clearly reduced DNIC in the majority of cases (21 of 26). Such a reduction was dose-related in the 0.6 to 2.5 microgram range and naloxone reversible; it plateaued within 90 min of microinjection. No clear relationship was found between the changes in DNIC and either the number of C-fiber-evoked spikes in the control sequences or the changes in the C-fiber responses induced by i.c.v. morphine. Autoradiographic controls using [3H]morphine showed a labeling along the ventricle wall including the hypothalamus, the periaqueductal gray matter and the floor of the 4th ventricle, three regions which have been implicated in the control of nociceptive transmission at the spinal level. Diffusion from the ventricle wall was over a distance of 0.5 mm and was identical whether observed 20 or 95 min after the microinjections.(ABSTRACT TRUNCATED AT 400 WORDS)